Vitamin D and autism: same old story?

I have to say that I wasn't all that surprised when I read the conclusions to the study by Eva Kočovská and colleagues [1] (open-access here) talking about significantly lower levels of 25-Hydroxyvitamin D3 (25(OH)D3) levels detected in their small cohort of young adults diagnosed with an autism spectrum disorder (ASD) compared with various control populations.

A deficiency or insufficiency of vitamin D - the sunshine vitamin/hormone - in relation to quite a few cases of autism is something that has been talked about more than once on this blog (see here). The value-added bit to the Kočovská findings was the suggestion that lower levels were detected "in young adolescents/adults with ASD" based in the Faroe Islands, where a lack of UVB exposure as a function of geographic position is to some extent compensated by "a diet rich in large oily fish containing vitamin D". I might add that this authorship group have talked vitamin D and autism in a previous paper [2].

The Kočovská paper is open-access but a few pointers might be in order:

• Young adults with autism, "their siblings and parents, and.. a typically-developing comparison group in the Faroe Islands" were the target populations under study as part of a wider investigation on the prevalence of autism in the Faroe Islands [3]. Blood draws "for [the] analysis of various environmental factors" enabled researchers to assay for vitamin D - 25(OH)D3 serum concentrations - by the gold standard that is mass spectrometry. The assay was apparently conducted here in Blighty.
• Results: "The ASD group had significantly lower levels of 25(OH)D3 [median (IQR) = 24.8 (27.5) nmol/L] compared to the healthy comparison group [median (IQR) = 37.6 (32.3) nmol/L], (95 % CI 5.0–22.5), p = 0.002 to their siblings [median (IQR) = 46.1 (28.3) nmol/L] (95 % CI 9.4–24.8), and parents [median (IQR) = 46.7 (36.2) nmol/L) (95 % CI 11.0–27.74], (p < 0.001 in both instances)". Of all participants in the ASD group, only 1 person had a result falling into the sufficiency range (≥75 nmol/L) and that seemed to be an outlier described as a female: "her 25(OH)D3 level was much higher than all other participants’ at 153 nmol/L".
• Quite a few participants from across the various control groups included for analysis were vitamin D deficient (58-65%). But: "In the ASD group, 88 % were vitamin D deficient". 
• Insofar as possible correlates, well, there was a "slight over-representation of spring births among the ASD group (32.5 %) and corresponding lowest level of vitamin D in this group". There was also a trend towards lower levels of vitamin D in males with ASD and their siblings. But diagnosis within the autism spectrum and scores on the ADOS showed no significant correlation.

The authors are rightly cautious about drawing too many conclusions from their results as they stand. They talk about low vitamin D levels in cases of autism potentially being linked to issues like being a picky eater [4] or "autism impacting on a family/child’s lifestyle" as per a preference for more indoor activities rather than those more likely to provide some sun exposure (see here). Body mass index (BMI) is also talked about as a function of the growing interest in vitamin D levels in those who are categorised as overweight or obese [5] which is something that continues to crop up in the autism research literature (see here). We can't also rule out some effect from comorbidity - ESSENCE as one of the Kočovská authors has described it - particularly in light of other research starting to talk about ADHD (attention-deficit hyperactivity disorder) and vitamin D deficiency (see here) and what seems to be emerging about the heightened comorbid prevalence of autism and ADHD (see here). Same also goes for something like depression too (see here) and its links with at least some autism [6]. Plenty of variables which have the ability to influence the Kočovská results.

But... on the back of previous studies indicating that vitamin D levels might be perturbed in some cases of autism I find myself similarly drawn to another conclusion reached by the authors: "the low vitamin D levels could be an indication of life-long vitamin D deficiency in ASD, and this hormone deficiency could, at least theoretically, have been involved in early aberrant development of the brain in these individuals, leading to the development of ASD". I say this acknowledging that Kočovská et al only looked at a single measurement of vitamin D and the evidence that maternal or cord blood levels of vitamin D don't seem to have much of an effect in this process as per the findings from Whitehouse and colleagues (discussed here) and some more recent work [7]. I don't think though anyone has actually tracked vitamin D levels across the child- and adulthood with autism in mind...

I might also draw your attention to a few other areas where vitamin D deficiency in cases of autism might also merit additional research... stop me if you've heard me talk about these before. So: autoimmunity and vitamin D levels as per the Mostafa findings (see here). GcMAF and vitamin D as per the Hornig/Lipkin patent application (see here). And then there is leaky gut and vitamin D (see here) in light of another area with some autism interest (see here); all worthy of further research consideration alongside further examination of those vitamin D receptors which are currently lacking in the autism research literature.

The news recently of "a remarkably consistent" relationship between "the lowest quintile of serum 25(OH)D concentration.. associated with increased all-cause and cardiovascular mortality" based on the findings from Schöttker and colleagues [8] (open-access here) is potentially pertinent. Without using scare tactics or anything like that, such findings should perhaps have special meaning in light of the Kočovská results and the news that over half of their autism cohort presented in the severe deficiency range (<25 nmmol/l). With no medical or clinical advice given or intended, I will draw your attention to the paper by Aloia and colleagues [9] (open-access) and the guidance they provide on potentially overcoming deficiency...

Music to close: Pulp and Common People. 

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[1] Kočovská E. et al. Vitamin D in the General Population of Young Adults with Autism in the Faroe Islands. J Autism Dev Disord. 2014 Jun 14.

[2] Kočovská E. et al. Vitamin D and autism: clinical review. Res Dev Disabil. 2012 Sep-Oct;33(5):1541-50.

[3] Kočovská E. et al. The rising prevalence of autism: a prospective longitudinal study in the Faroe Islands. J Autism Dev Disord. 2012 Sep;42(9):1959-66.

[4] Cermak SA. et al. Food selectivity and sensory sensitivity in children with autism spectrum disorders. J Am Diet Assoc. 2010 Feb;110(2):238-46.

[5] Vimaleswaran KS. et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013;10(2):e1001383.

[6] Matson JL. & Williams LW. Depression and mood disorders among persons with Autism Spectrum Disorders. Res Dev Disabil. 2014 May 23;35(9):2003-2007.

[7] Keim SA. et al. Maternal and Cord Blood 25(OH)-Vitamin D Concentrations in Relation to Child Development and Behaviour. Paediatr Perinat Epidemiol. 2014 Jun 17.

[8] Schöttker B. et al. Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States. BMJ. 2014 Jun 17;348:g3656.

[9] Aloia JF. et al. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr. 2008 Jun;87(6):1952-8.

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Kočovská E, Andorsdóttir G, Weihe P, Halling J, Fernell E, Stóra T, Biskupstø R, Gillberg IC, Shea R, Billstedt E, Bourgeron T, Minnis H, & Gillberg C (2014). Vitamin D in the General Population of Young Adults with Autism in the Faroe Islands. Journal of autism and developmental disorders PMID: 24927807

More suramin and autism [mouse] findings

The headline: 'Century-old drug reverses signs of autism in mice' brought the paper by Jane Naviaux and colleagues [1] (open-access) to my attention and some slightly familiar work (see here) on the use of suramin in a mouse model of autism, or rather a mouse model of maternal immune activation. Indeed, I seem to remember that the previous study by this group [2] courted similar publicity, with some familiar headlines...

Not lecturing... @ Wikipedia 

The latest offering from Naviaux et al is not so dissimilar from their previous work on that mouse model of autism, this time testing "the hypothesis that the behavioral manifestations of the MIA [maternal immune activation] model are a consequence of pathological persistence of the evolutionarily conserved CDR [cell danger response]... and that the CDR is maintained by dysregulated purine metabolism and secondary abnormalities in purinergic signaling". The press release about the study can be viewed here.

What this all translates into is that a state of immune arousal above and beyond what would be typically expected during pregnancy is somehow impacting on offspring development pertinent to an elevated risk of conditions like autism or schizophrenia. There is quite a bit of literature on this topic from the autism perspective (see here) and based on animal models other than just rodents (see here). The cell danger response (CDR) described by Naviaux (Robert that is) [3] represents "the evolutionarily conserved metabolic response that protects cells and hosts from harm". Indeed that last reference [3] contains just about every biological link known to autism science at the current time... including mitochondria. The idea is that triggering immune activation activates "a conserved cellular response to stress" called the CDR and the proposed master regulator of the CDR is purinergic signalling [4] - "purine nucleotides and nucleosides as extracellular messengers". ATP (adenosine triphosphate) as well as being quite an important molecular fuel source, is suggested to be one of the nucleotides which "can bind to cell surface receptors and act as signaling molecules and neuromodulators that are important in inflammation.. neurotransmission.. and many other biological processes".

A few basic points about the Naviaux study:

• Mice were the lucky volunteers for this study, and again the 'good breeder' that is the C57BL/6J variety. As per their previous trial, pregnant female mice were given something to artificially stimulate their immune system and "initiate the MIA model" or a saline control and then their offspring were the study focus.
• Suramin or saline (as a control) was then administered to 6-month old offspring mice and thereafter "behaviors were evaluated". Suramin levels were also examined, as were a broad range of metabolites as part of some metabolomic analysis based on the use of triple quad mass spectrometry.
• Results: "MIA animals showed social deficits from an early age". Nothing too novel there bearing in mind previous observations in this area of research. But... "Single-dose APT [antipurinergic therapy] with suramin completely reversed the social abnormalities in 6.5-month-old adults". Social behaviour by the way, was quantified as "time spent interacting with a novel ("stranger") mouse".
• The benefit of suramin also lasted for quite a while: "a small residual benefit to social behavior was still detectable" even after 5 weeks following the intervention. There is some discussion by the authors about this effect; noted to be potentially "due to the development of metabolic memory and/or somatic epigenetic DNA changes that lasted longer than the physical presence of the drug".
• Then the biochemistry. Suramin seemed to by-pass that very important gateway, the blood-brain barrier (BBB) and end up in the brainstem following some analysis of sacrificed offspring mice: "consistent with the notion that nuclei in brainstem, or their projection targets in distant sites of the brain, may mediate the dramatic behavioral effects of acute and chronic APT in this model".
• And more: "Comprehensive metabolomic analysis revealed disturbances in several other metabolic pathways relevant to children with ASDs. These included disturbances in microbiome, phospholipid, cholesterol/sterol, sphingolipid, glycolytic and bile salt metabolism". This bearing in mind that only "male animals that had been behaviorally evaluated were tested". Purine metabolism and the gut microbiome seemed to be quite important to the author's results. At this point I'll refer you back to the work by Elaine Hsiao and colleagues... 
• Moreover: "The top, non-microbiome-associated metabolite was quinolinic acid... which was decreased in the MIA model". Quinolinic acid implies the involvement of one of those aromatic amino acids, tryptophan, which is an autism research favourite [5]. More than that is the literature on the intersecting kynurenine pathway and how that might relate to a condition like schizophrenia (see here).
• The authors caution that their results are (a) mouse based and (b) "suramin is a poor drug choice for chronic use because of potentially toxic side effects that can occur with prolonged treatment". That being said, they do suggest that "new drugs might be given only once, or intermittently, during sensitive windows to unblock metabolism, restore more normal neural network function, improve resilience and plasticity, and permit improved development in response to behavioral and interdisciplinary therapies, and to natural play". Just in case you'd like an alternative reading of this study, have a look at this write-up too.

I do apologise for all the quotes taken from the Naviaux paper and used in this post, but when the authors say it better than I could, why would I try and complicate things any further? Indeed, the more I read the paper by Naviaux and colleagues, the more I see what a potential gem it actually is. I say this based on the pretty comprehensive way that the authors went about looking at the MIA model and the effect of their intervention, crossing behavioural (mouse behavioural) and biochemical fields. Mention of the words 'microbiome' and 'metabolome' are also guaranteed to perk my interest. All that enthusiasm is however tempered dependent on the work being replicated and not just in a mouse model either.

A few closing comments are all that are required. Looking at the list of biochemical pathways altered in the MIA model of autism (see Table 1 here) we see lots of familiar names too numerous to mention. Outside of looking at the effect of suramin on these pathways, I'm minded to suggest that other interventions might also benefit from some similar inspection of their effects on said pathways. Even as one commentator has already noted: "[The findings] are valuable, but the main problem is that they rely on a model of immune infection, not a genuine model of autism... They should have tested one of the classical models of autism... meaning genetic models of autism — to see whether suramin indeed corrects autistic behaviors".

I've also not really gone into the detail when it comes to the cell danger response (CDR) in this post because it is a complicated area and seems to tie into various issues which are slightly beyond my level of expertise. I would like to bring in the letter by Theoharides [6] at this point however, and his discussion linking "extracellular mitochondrial material" to mast cell activation (see here) on the back of the previous study by this authorship group, as another area crying out for further investigation.

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[1] Naviaux JC. et al. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Translational Psychiatry. 2014; 4: e400; doi:10.1038/tp.2014.33

[2] Naviaux RK. et al. Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PLoS One. 2013;8(3):e57380.

[3] Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014 May;16:7-17.

[4] Burnstock G. Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol Rev. 2006 Mar;58(1):58-86.

[5] Boccuto L. et al. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism. 2013 Jun 3;4(1):16.

[6] Theoharides TC. Extracellular Mitochondrial ATP, Suramin, and Autism? Clinical Therapeutics. 2013; 35: 1454-1456.

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Naviaux JC, Schuchbauer MA, Li K, Wang L, Risbrough VB, Powell SB, & Naviaux RK (2014). Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Translational psychiatry, 4 PMID: 24937094

The developmental regression rate and autism

I have already made mention of the paper by Robin Goin-Kochel and colleagues [1] in a previous post on the topic of developmental regression and autism (see here). On that occasion it was to substantiate that approximately 40% of children diagnosed as being on the autism spectrum were reported to have shown some kind of developmental regression as part and parcel of their presentation. Given however the assertion in the Goin-Kochel paper about using "the largest, most comprehensively phenotyped sample to date" reflecting their participant numbers (N=2105) derived from the Simons Simpex Collection (SSC), I thought it worthwhile to include a separate blog entry for this important paper.

I'm pretty sure that the topic of developmental regression and autism needs no further introduction. Suffice to say that as the name suggests, it's all about a loss of previously acquired skills and how this might map on to some of those 'autisms' that I seem to talk about quite a lot. After a bit of a laboured start (see here) there is now a general acceptance that regression can occur in cases of autism and sometimes pretty rapidly (see here) although I hasten to add, not seemingly present for everyone with autism.

I have to thank Natasa for passing me a full-text copy of the Goin-Kochel paper, and without further ado, here are a few of the main points:

• The SSC was the source for participants, which meant that diagnoses of autism or autism spectrum disorder (ASD) were about as reliable as one could hope for. Interestingly, the authors do make mention of the whole DSM-IV to DSM-5 transition and what that might mean for databases such as the SSC but that's perhaps fodder for another day.
• "Regression was operationalized using the skill-loss items from both the ADI-R and a supplemental interview that captured information about additional and more subtle skill losses". I've talked before about how ADI-R was a really important contributor to raising the profile of regression and autism as a function of it including items about 'loss of language/other skills'. In this case, researchers defined various types of 'loss' to include codings such as 'full losses' and 'subthreshold losses'. They also analysed data according to "skill loss at/before 36 months and those who experienced skill loss after 36 months".
• Results: "Overall, 36.9% of children had some type of regression". Such regression included a regression in language and/or other skills and included those with full losses and those with subthreshold losses. Another quote: "When combined, 585 (27.8%) children experienced some degree of language loss and 568 (27.0%) experienced some degree of other loss".
• The authors focused quite a lot on the pre-36 months loss side of things as a function of quite a lot of discussion on age of first parental concern being rooted in that critical period. So: "those with any degree of language loss (full or subthreshold) at/before 36 months scored significantly lower than those with no language loss" when looking at how regression might affect "cognitive and adaptive-functioning outcomes". 
• Finally, a couple of other important details to mention: (a) "subthreshold losses of other skills occurred later than any type of language regression and later than full losses of other skills", and (b) duration of loss of skills is also discussed: "most children regained their skills by 3.5-5 years of age". They conclude that their study: "lends support to the argument that children whose parents report regression represent a distinct ASD subtype that may be associated with lower cognitive functioning".

The participant group size and the use of the SSC are important features which make these results something to shout about. Alongside the meta-analysis by Barger and colleagues [2] autism research is beginning to build up quite a good picture on the rate of regression being reported in the autism research literature and some details on presentation and even outcome.

That being said, there is still an awful lot more to do in this area. The Goin-Kochel did not set out to look at "etiological mechanisms" but the next stage in this research should surely be further study which looks at possible correlates to such regressive accounts. I wouldn't necessarily agree with the sentiments of the authors when they say: "An acknowledged limitation of this study is its reliance on parent-report data" especially when it comes to parent report and other issues such as gastrointestinal (GI) problems (see here) and the conclusions reached by Phillip Gorrindo and colleagues [3] (open-access here). Recall may well be affected by things like telescoping effects (see here) but in these days of home movies [4] and the rise of social media, many infants see the end of camera lens very, very early following their entry into the big wide world. Where regression occurs, I'm sure many parents would have their own ideas about the hows and whys which could be investigated including some slightly more biological / genetic based investigations [5].

I've two more points to make on this study and research area and that's all. First is an issue which the authors touch upon in their discussion of their results: "... the SSC is largely comprised of Caucasian families". The recent abstract from Adiaha Spinks-Franklin and colleagues (which, at the time of writing, I don't yet think is published in a peer-reviewed form) hints at some racial differences in the occurrence of regression in autism. The question is whether this might also translate into a different pattern of regressive symptoms and indeed, any different effects on longer term outcome?

Second is that issue of long-term outcome. As we're starting to see with the optimal outcome work (see here), longitudinal studies looking at outcome from all those developmental trajectories which make up the autisms is starting to yield some interesting results. The next question would be whether similar studies looking at regressive vs. non-regressive presentation (even different types of regression [6]) would similarly provide important data on the extent to which regression might affect future development and presentation and ways these could be positively affected. I'd also add that looking at any effects from regression on comorbidity outside of the core dyad of symptoms might also be included in any future work knowing what we (think we) know about this important issue.

To close, Katy Perry and Last Friday Night (a song my brood are really enjoying at the moment).

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[1] Goin-Kochel RP. et al. Developmental regression among children with autism spectrum disorder: Onset, duration, and effects on functional outcomes. Res Autism Spectr Disord. 2014; 8: 890-898.

[2] Barger BD. et al. Prevalence and onset of regression within autism spectrum disorders: a meta-analytic review. J Autism Dev Disord. 2013 Apr;43(4):817-28.

[3] Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

[4] Palomo R. et al. Autism and family home movies: a comprehensive review. J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S59-68.

[5] Shoffner J. et al. Fever plus mitochondrial disease could be risk factors for autistic regression. J Child Neurol. 2010 Apr;25(4):429-34.

[6] Ozonoff S. et al. Parental report of the early development of children with regressive autism: the delays-plus-regression phenotype. Autism. 2005 Dec;9(5):461-86.

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Goin-Kochel, R., Esler, A., Kanne, S., & Hus, V. (2014). Developmental regression among children with autism spectrum disorder: Onset, duration, and effects on functional outcomes Research in Autism Spectrum Disorders, 8 (7), 890-898 DOI: 10.1016/j.rasd.2014.04.002

What factors influence the age of autism diagnosis?

Old man @ Wikipedia 

The paper by Ram Mishaal and colleagues [1] examining some of the multitude of variables which might influence how early or late a child receives a diagnosis of autism provides the starting point for today's post. Based on the analysis of over 500 children diagnosed with an autism spectrum disorder (ASD), the authors found that: "the severity of the social interaction impairment reported by the parents and having a history of developmental regression was associated with an earlier age of ASD diagnosis". They also reported that a child having an older sibling was associated with earlier diagnosis. Conversely, they concluded that: "the severity of the restricted and repetitive behaviors was associated with delayed age of ASD diagnosis". I'll come back to some of these points shortly.

In these days of calls for ever earlier identification, diagnosis and intervention where autism is concerned, it is still a stark reality for many that autism [in childhood] is diagnosed at a much later point from where initial concerns were raised/detected. Of course, one has to take into account issues around the plurality of autism (see here) and that there may be stability issues with the early days of some autism presentation (see here). But still diagnosis can be a long and drawn out process; sometimes even adversely influenced by the views and opinions of clinicians themselves (see here) despite there being some [very] NICE guidance available, at least for parts of the UK.

During the early years of my research career I remember my go-to study on the topic of age at autism diagnosis was the report by Howlin & Asgharian [2] and their findings: "In the 'autism group' the average age when diagnosis was confirmed was around 5.5 years; in the 'Asperger group' it was 11 years" based on a UK-based sample of nearly 800 families in the late 1990s. Unfortunately, even in the following years, things seem to have got only marginally better when it comes to age at diagnosis as per the report by Mandell and colleagues [3] (64.9 months for all ASDs) and indeed, some of our own data [4]. The latest CDC estimates of autism in the US (see here) reported by Wingate and colleagues [5] does however hint that things might be continuing to move in the right direction as per their findings: "Although ASD is sometimes diagnosed by 2 years of age, the median age of the first ASD diagnosis remains older than age 4 years in the ADDM Network communities". This bearing in mind the different geographical locations of these studies and different processes in place leading up to diagnostic assessment.

To the question then of what factors might influence age of diagnosis outside of just resource issues (similar to the diagnosis of autism in adults), there are some clues from the collected literature which I'm gonna cherry pick. Bear in mind though, that there is no one-size-fits-all formula when it comes to answering this important question.

• Daniels & Mandell [6] surveyed some of the collected literature in this area. Perhaps unsurprisingly "greater symptom severity" was one of the core factors associated with earlier diagnosis. Some of this authorship group have gone into further detail about which symptoms might affect age and diagnosis [7]. On that occasion they concluded that: "Children with severe language deficits received a diagnosis an average of 1.2 years earlier than other children. Hand flapping, toe walking, and sustained odd play were associated with a decrease in the age of diagnosis, whereas oversensitivity to pain and hearing impairment were associated with an increase".
• Frenette and colleagues [8] in their study reported that: "a one year increase in maternal age at delivery was associated with a 0.06 decrease in age at ASD diagnosis". So there might be something of a correlation between older mums and earlier diagnosis. This suggests one or more factors might pertain: (a) older mums with more 'life experience' and perhaps with a greater likelihood of having other children, might be more sensitive to symptoms, or (b) younger mums with less 'life experience' might be less sensitive to symptoms. Right or wrong, that's my interpretation anyway, and certainly, it was something noted by Fountain and colleagues [9] (open-access here).
• The paper by Rosenberg and colleagues [10] (open-access here) did not find any one factor as being linked to age at diagnosis. That being said they did suggest that: "Both ID [intellectual disability] and history of autistic regression were associated with earlier AOD [age of initial diagnosis]". They similarly noted the differences in age at diagnosis between different diagnoses on the autism spectrum. Race and gender was also picked up.
• Ethnicity was also something picked up in the study by Coo and colleagues [11] (open-access here). They noted that: "rural residence, diagnosis in more recent years, and foreign birthplace were associated with a later age at diagnosis". They continue: "Children who are visible minorities or who have siblings with ASD were more likely to be diagnosed earlier". Not everyone however agrees with those sentiments as per the paper by Valicenti-McDermott and colleagues [12].

I think what we can take from this collected data is that there are many influences pushing and pulling at the age of diagnosis of autism outside of the levels of resources available and other population factors. Presentation of symptoms in terms of timing and severity are the obvious factors which seem to influence age at diagnosis. Regression in symptoms, as I've talked about a few times on this blog (see here and see here) probably depends on how severe the regression was and when it happened.

Outside of the continued need for early and accurate diagnosis, there are other important implications from any change in age at diagnosis. So for example, the potential to affect autism prevalence estimates as per the conclusions by Parner and colleagues [13] is something to consider. Whether also early diagnosis and by assumption, early intervention might also have some important effects on say, the likelihood of joining that optimal outcome group (see here) is another consideration too.

Music to close. Please do not mention the football. Or as someone noted for fans of the England football (soccer) team "that familiar sense of utter disappointment. Hello old friend". So instead a 'sit back and enjoy the summer' song: Waves.

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[1] Mishaal RA. et al. Age of autism spectrum disorder diagnosis is associated with child's variables and parental experience. Res Autism Spect Disord. 2014; 8: 873-880.

[2] Howlin P. & Asgharian A. The diagnosis of autism and Asperger syndrome: findings from a survey of 770 families. Dev Med Child Neurol. 1999 Dec;41(12):834-9.

[3] Mandell DS. et al. Age of diagnosis among Medicaid-enrolled children with autism, 2001-2004. Psychiatr Serv. 2010 Aug;61(8):822-9.

[4] Whiteley P. et al. Trends in Developmental, Behavioral and Somatic Factors by Diagnostic Sub-group in Pervasive Developmental Disorders: A Follow-up Analysis. Autism Insights. 2009; 1: 3-17.

[5] Wingate M. et al. Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ. 2014 Mar 28;63(2):1-21.

[6] Daniels AM. & Mandell DS. Explaining differences in age at autism spectrum disorder diagnosis: A critical review. Autism. 2013 Jun 20.

[7] Mandell DS. et al. Factors associated with age of diagnosis among children with autism spectrum disorders. Pediatrics. 2005 Dec;116(6):1480-6.

[8] Frenette P. et al. Factors affecting the age at diagnosis of autism spectrum disorders in Nova Scotia, Canada. Autism. 2013 Mar;17(2):184-95.

[9] Fountain C. et al. Age of diagnosis for autism: individual and community factors across 10 birth cohorts. J Epidemiol Community Health. 2011 Jun;65(6):503-10.

[10] Rosenberg RE. et al. Factors affecting age at initial autism spectrum disorder diagnosis in a national survey. Autism Res Treat. 2011;2011:874619.

[11] Coo H. et al. Correlates of age at diagnosis of autism spectrum disorders in six Canadian regions. Chronic Dis Inj Can. 2012 Mar;32(2):90-100.

[12] Valicenti-McDermott M. et al. Age at diagnosis of autism spectrum disorders. J Pediatr. 2012 Sep;161(3):554-6.

[13] Parner ET. et al. Autism prevalence trends over time in Denmark: changes in prevalence and age at diagnosis. Arch Pediatr Adolesc Med. 2008 Dec;162(12):1150-6.

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Mishaal, R., Ben-Itzchak, E., & Zachor, D. (2014). Age of autism spectrum disorder diagnosis is associated with child's variables and parental experience Research in Autism Spectrum Disorders, 8 (7), 873-880 DOI: 10.1016/j.rasd.2014.04.001

Blocking FRAAs and thyroid function in autism

FRAAs - folate receptor alpha autoantibodies - may correlate with reduced thyroid function in cases of autism is the primary finding from the paper by Richard Frye and colleagues [1] (open-access). And immediately my attention is piqued at the possibility of a link...

FRAAs have been mentioned before on this blog (see here) based on a really interesting paper by the autism research tag team that is Frye and Rossignol [2] who continue to give when it comes to peer-reviewed research on autism. On that occasion, they reported: "serum FRA [folate receptor α autoantibodies] concentrations were measured in 93 children with ASD [autism spectrum disorder] and a high prevalence (75.3%) of FRAs was found". The net result was that there may be issues with the availability of folate, and as in the condition cerebral folate deficiency (CFD), there may be some use in looking at folinic acid (leucovorin) to normalise levels of 5-methyltetrahydrofolate. But please note I'm advocating nothing on this blog just describing findings.

In their most recent paper, Dr Frye and colleagues took things one stage further:

• Levels of blocking and binding FRAAs were measured from serum samples donated by 32 children diagnosed with an autism spectrum disorder (ASD). Based on participants' medical records, levels of thyroid stimulating hormone (TSH) were "abstracted" and correlated with FRAAs measures.
• Results: bearing in mind this was a 'let's see' study with no control groups and TSH values derived from medical records, the authors reported: "No significant relationship was found between the binding FRAA and TSH. However, a higher blocking FRAA titer was significantly related to a higher TSH concentration". The correlation (r) came out at 0.36, which is OK but not necessarily what one might call a strong relationship.
• They add: "Patients who were positive for the blocking FRAA were found to have a significantly higher TSH concentration as compared to patients who were negative for the blocking FRAA". 

There are a few other points to comment on in this paper. First is the focus on thyroid function and autism. I've talked a few times about maternal thyroid levels and how they may correlate to some extent with autism risk (see here and see here). The research literature on thyroid levels in people with autism is slightly more scant (see here), and bearing in mind that there are various other thyroid measures that might be relevant, the focus on TSH alone rather limits the conclusions one can draw about thyroid function in this study. Indeed, none of the participants in this sample had "an abnormally low TSH" result and only a few had "abnormally elevated TSH".

Allied to thyroid function, and mentioned by Frye et al is the issue of iodine deficiency, which again, has been mentioned on this blog with autism in mind (see here). Iodine plays an important role in the production of thyroid hormones. Unfortunately the current study did not assay for iodine levels so we are to some extent left in the dark about any role.

There's little more for me to say about this trial outside of the need for studies looking at rather more direct measures, and a few more of them particularly pertinent to the functions of the thyroid in an autism group. I might also add that in view of the suggestion that a milk-free diet "downregulates folate receptor autoimmunity" as per the work by Ramaekers and colleagues [3] (open-access) looking at CFD, future research might also assess any effect this might have on any thyroid link too. Got milk (opioid peptides)?

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[1] Frye RE. et al. Folate receptor alpha autoantibodies modulate thyroid function in autism spectrum disorder. NAJMS 2014; 7: 53-56.

[2] Frye RE. et al. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013; 18: 369-381.

[3] Ramaekers VT. et al. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol. May 2008; 50(5): 346–352.

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Richard E. Frye, Jeffrey M Sequeira, Edward Quadros, & Daniel A. Rossignol (2014). Folate receptor alpha autoantibodies modulate thyroid function in autism spectrum disorder N A J Med Sci. , 7 (2), 53-56 : 10.7156/najms.2014.0702053

Optimal outcome and autism: a role for intervention?

Optimal outcome and autism.

Not here you don't @ Wikipedia 

I'm sure most people with an eye on autism research and practice will have come across this issue. The idea is that in amongst the various developmental trajectories which are being realised in these days of autisms over autism, there may be some children previously diagnosed with an autism spectrum disorder (ASD) who move outside of the diagnostic boundaries of the condition.

There is still lots of debate about the hows and whys of this scenario [1], and in particular, whether leaving the autism diagnostic label behind means everything about autism is left behind (see here). But certainly it is getting more and more difficult to dispute the fact that [some of] the signs and symptoms of autism are anything but static [2] and for some at least, the diagnostic label of autism might not be as lifelong as previously thought. Even the recent IMFAR conference saw some continued interest in this issue (see here).

Today I want to introduce a couple of papers which add to the literature on optimal outcome (OO) and autism, and in particular move away from just description to looking at what factors might potentially influence optimal outcome and specifically a possible role for intervention. You might consider this post an extension of an entry not-so-long-ago (see here) talking about the findings from Deborah Anderson and colleagues [3].

The paper by Nahit Motavalli Mukaddes and colleagues [4] (open-access) adds to the increasing literature on optimal outcome and autism with their assertion that: "High IQ and the development of communicative and language skills at an early age could be the most powerful factors contributing to an optimal outcome". The paper is open-access but a few points are noteworthy:

• Based in Turkey, this was a descriptive study of some 39 children "who previously received a diagnosis of ASD and who did not meet the criteria for any ASD in the final examination". Importantly, the authors held pretty detailed records on this group based on their initial assessment and diagnosis for autism including "an in-depth psychiatric examination of the child" which meant plenty of face-to-face contact accompanied by an analysis of medical history. 
• They also followed children "every 3-4 months" following their referral to an education program "inspired by Pivotal Response Training (PRT)". Most children followed PRT although 2 children "were able to attend ABA [Applied Behaviour Analysis] programs with frequencies ranging from as low as 8 hours per week up to the recommended 20 hours per week".
• Optimal outcome was specifically defined in this study based on the paper by Helt and colleagues [5] slightly modified. This included both abatement of autistic symptoms and IQ also being measured in the 'normal' range.
• Results: Well, aside from talking about communication and IQ as being potentially important factors related to optimal outcome: "The time from baseline to optimal outcome was 2.71 ± 1.76 years (range: 0.5-8 years)". The mean age at optimal outcome was round about 5 years old although there was some variation around these variables.

The authors provide quite a bit more detail on their study and why their results might be considered credible. I note they also suggest that comorbid medical disorders such as epilepsy were largely absent from this group and might "be another factor that influences outcomes". I'd chime in here and agree with that sentiment in light of what we know about the autism-epilepsy relationship (see here) and specifically the growing realisation that IQ or cognitive ability seems to be an important factor, confirmed by Jokiranta and colleagues [6]. The issue of intervention type and specifically whether something like ABA might play a role in optimal outcomes leads me on to the next study.

The paper by Alyssa Orinstein and colleagues [7] adds even further to the collected literature in this area, daring again to talk about what intervention might show involvement with a small group of optimal outcomers compared with those categorised as being high-functioning autism (HFA). Deborah Fein, the godmother of optimal outcome is also a co-author on this study.

So:

• "The current study examined intervention histories in 25 individuals with OO and 34 individuals with HFA (current age, 8-21 years), who did not differ on age, sex, nonverbal intelligence, or family income. Intervention history was collected through detailed parent questionnaires". 
• Those letters A-B-A were again mentioned in the results: "Substantially more children with OO than HFA received applied behavior analysis (ABA) therapy, although for children who received ABA, the intensity did not differ between the groups".
• Likewise that issue of comorbid conditions likely rears its head in this study too: "Children in the HFA group were more likely to have received medication, especially antipsychotics and antidepressants".
• One final quote to make at the risk of plagiarising the whole abstract: "There were no group differences in the percent of children receiving special diets or supplements".

ABA seems to do rather well in both the Mukaddes and Orinstein studies in relation to optimal outcome. I know that as an intervention it's not everyone's cup of tea, particularly with some rather chequered history, but there are 'moderates' out there who support the principles of ABA (see here) and the evidence base is not bad compared to lots of other interventions put for improving outcome in relation to autism. Without nailing my colours to any particular mast, I'd echo the sentiments of Orinstein et al and their suggestion of more to do - prospective studies - in this area. I might also draw your attention to other findings on PRT and ABA which might also be pertinent [8].

I'll also pass some comment on the use of the words 'special diets' when it comes to the Orinstein paper. I assume special diets includes things like the gluten- and casein-free (GFCF) diet and goes some way to addressing the notion that the optimal outcome group are not over-represented by those following such an intervention. I'd agree with that sentiment knowing what I think I know about this particular intervention. There is of course another way of looking at this insofar as there being best responders to something like a GFCF diet included in the optimal outcome group... but let's not get too carried away just yet.

'Optimal outcome' with autism in mind still has the ability to divide opinion. Reading again the editorial by Sally Ozonoff (see here) which accompanied the original Fein study and the description from Uta Frith on "a variant that is temporary" (see here) makes me realise that sometimes the bigger job of science is not actually doing and reporting the work, but altering long and often passionately held views and opinions as a result of that new knowledge. As intimated on a previous post talking about the economics of autism (see here), although I am not a great fan of talking about 'what autism costs' and the potentially unhelpful way that headlines like 'Autism costs '£32bn per year' in UK' can be construed, the findings from the Mukaddes and Orinstein studies should perhaps be the topic of further autism research. Not only because they might further highlight who is most likely to fall into the OO category and how they might arrive there but as per the paper by Barrett and colleagues [9] the onward implications to public finances with the aim to: "leverage investment in education and intervention to mitigate aspects of autism spectrum disorder that negatively impact individuals with the disorder and their families".

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[1] Bölte S. Is autism curable? Dev Med Child Neurol. 2014 May 20.

[2] Wodka EL. et al. Predictors of phrase and fluent speech in children with autism and severe language delay. Pediatrics. 2014; 131: e1128-e1134.

[3] Anderson DK. et al. Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. J Child Psychol Psychiatry. 2014 May;55(5):485-94.

[4] Mukaddes NH. et al. Characteristics of Children Who Lost the Diagnosis of Autism: A Sample from Istanbul, Turkey. Autism Res Treatment. 2014: 472120.

[5] Helt M. et al. Can children with autism recover? If so, how? Neuropsychol Rev. 2008 Dec;18(4):339-66.

[6] Jokiranta E. et al. Epilepsy Among Children and Adolescents with Autism Spectrum Disorders: A Population-Based Study. J Autism Dev Disord. 2014 May 7.

[7] Orinstein AJ. et al. Intervention for optimal outcome in children and adolescents with a history of autism. J Dev Behav Pediatr. 2014 May;35(4):247-56.

[8] Mohammadzaheri F. et al. A Randomized Clinical Trial Comparison Between Pivotal Response Treatment (PRT) and Structured Applied Behavior Analysis (ABA) Intervention for Children with Autism. J Autism Dev Disord. 2014 May 20.

[9] Barrett B. et al. Comparing service use and costs among adolescents with autism spectrum disorders, special needs and typical development. Autism. 2014 Jun 9.

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Mukaddes, N., Tutkunkardas, M., Sari, O., Aydin, A., & Kozanoglu, P. (2014). Characteristics of Children Who Lost the Diagnosis of Autism: A Sample from Istanbul, Turkey Autism Research and Treatment, 2014, 1-10 DOI: 10.1155/2014/472120



Orinstein AJ, Helt M, Troyb E, Tyson KE, Barton ML, Eigsti IM, Naigles L, & Fein DA (2014). Intervention for optimal outcome in children and adolescents with a history of autism. Journal of developmental and behavioral pediatrics : JDBP, 35 (4), 247-56 PMID: 24799263